Abstract

Geldanamycin (GDM) has been modified by different type neutral/acidic/basic substituents (1–7) and by quinuclidine motif (8), transformed into ammonium salts (9–13) at C(17). These compounds have been characterised by spectroscopic and x-ray methods. Derivative 8 shows better potency than GDM in MCF-7, MDA-MB-231, A549 and HeLa (IC₅₀s = 0.09–1.06 µM). Transformation of 8 into salts 9–13 reduces toxicity (by 11-fold) at attractive potency, e.g. MCF-7 cell line (IC₅₀∼2 µM). Our studies show that higher water solubility contributes to lower toxicity of salts than GDM in healthy CCD39Lu and HDF cells. The use of 13 mixtures with potentiators PEI and DOX enhanced anticancer effects from IC₅₀∼2 µM to IC₅₀∼0.5 µM in SKBR-3, SKOV-3, and PC-3 cancer cells, relative to 13. Docking studies showed that complexes between quinuclidine-bearing 8–13 and Hsp90 are stabilised by extra hydrophobic interactions between the C(17)-arms and K58 or Y61 of Hsp90.

摘要

格尔德霉素（GDM）已经由不同类型的中性/酸性/碱性取代基（修改17）和奎宁环基序（8），转化为铵盐（9 - 13在C（17））。这些化合物已通过光谱和 X 射线方法表征。衍生物8在 MCF-7、MDA-MB-231、A549 和 HeLa 中显示出比GDM更好的效力（IC ₅₀ s = 0.09–1.06 µM）。将8转化为盐9 – 13以有吸引力的效力降低毒性（降低 11 倍），例如 MCF-7 细胞系 (IC ₅₀∼2 µM)。我们的研究表明，在健康的 CCD39Lu 和 HDF 细胞中，与GDM相比，较高的水溶性有助于降低盐的毒性。使用13分的混合物与增效剂PEI和DOX增强从IC抗癌作用₅₀〜2μM至IC ₅₀〜0.5μM在SKBR-3，SKOV-3，和相对于PC-3肿瘤细胞，13。对接研究表明之间的复合物的奎宁环轴承8 - 13和Hsp90的由C（17）和-arms Hsp90的K58或Y61之间的额外的疏水相互作用稳定。